Methods, systems, and software program for validation and monitoring of pharmaceutical manufacturing processes

ABSTRACT

Methods, systems, and software program for validation of pharmaceutical manufacturing processes and quality assurance process are described and disclosed herein. Consequently, the methods provide a means to perform validation on an integrated level whereby the quality control unit can ensure data and product integrity and minimize cost.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 11/500,642, filed 8Aug. 2006, which is a continuation of U.S. Ser. No. 10/840,732, filed 6May 2004. The contents of which are fully incorporated by reference.

STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH

Not applicable.

FIELD OF THE INVENTION

The invention described herein relates to methods, systems, and softwareprogram that are modified for use in software and hardware validation ofpharmaceutical manufacturing processes. The invention further relates tothe enhancement of quality assurance implementation protocols in currentgood manufacturing practice in manufacturing, processing, packing,and/or holding of drugs.

BACKGROUND OF THE INVENTION

Over the last two decades, significant changes in the environment ofpharmaceutical regulation have occurred and have resulted in incrementaladjustments in regulatory approaches to product quality. These changesincluded an increased number of pharmaceutical products and a greaterrole of medicines in health care, decreased frequency of manufacturinginspections as a result of fewer resources available for pharmaceuticalmanufacturing inspections, accumulation of experience with, “and lessonslearned from”, various approaches to the regulation of product quality,advances in the pharmaceutical sciences and manufacturing technologies,application of biotechnology in drug discovery and manufacturing,advances in the science and management of quality and, globalization ofthe pharmaceutical industry. The cumulative impact of these changes hasbeen greater than the sum of the parts and there is an industry wideneed to develop integrated approaches to monitor and assess thevalidation of processes and overall quality of products provided to endusers and patients.

Looking ahead the most up-to-date concepts of risk management andquality systems approaches should be incorporated while continuing toensure product quality. The latest scientific advances in pharmaceuticalmanufacturing and technology are encouraged. Additionally, thesubmission review program and the inspection program should operate in acoordinated and synergistic manner and regulation and manufacturingstandards should be applied consistently. The management of validationand quality assurance programs should encourage innovation in thepharmaceutical manufacturing sector in order to provide the mosteffective public health protection. Resource limitations preventuniformly intensive coverage of all pharmaceutical products andproduction. Significant advances in the pharmaceutical sciences and inmanufacturing technologies have occurred over the last two decades.While this knowledge has been incorporated in an ongoing manner intoproduct quality regulation, the fundamental nature of the changesdictates a thorough evaluation of the science base to ensure thatproduct quality assurance and validation not only incorporatesup-to-date science, but also encourages further advances in technology.Integrated quality systems orientation principles from variousinnovative approaches to manufacturing quality that have been developedin the past decade should be evaluated for applicability and cGMPrequirements and related pre-approval requirements should be evaluatedaccording to applicable principles. In addition, interaction of thepre-market CMC review process and the application of cGMP requirementsshould be evaluated as an integrated system.

With the globalization of pharmaceutical manufacturing requires a globalapproach to integration keeping in mind the overall objective of strongpublic health protection. To accomplish these needed goals there is aneed to carry out the following actions. The artisan should use emergingscience and data analysis to enhance validation and quality assuranceprograms to target the highest risk areas. From the aforementioned, theevaluation of the feasibility of establishing dedicated and integratedcadres of pharmaceutical validation and quality assurance experts shouldbecome readily apparent to one of ordinary skill in the art. Alsoapparent to one of ordinary skill in the art is the ability to provide acost-efficient network of validation and quality assurance protocols. Byproviding an integrated and user friendly approach to validation andquality assurance the overall benefit to the public at-large ispharmaceutical end products available at lower costs. This is turn willallow more persons or animals to benefit from innovations that occur inthe treatment of disease. Additionally, there is also a need to usethese modalities as research tools to monitor, assess, and further thestate of the art in all areas of life science treatment and studies,specifically biotechnology and pharmaceuticals.

SUMMARY OF THE INVENTION

The invention provides for a software program that validates devicesused in the manufacture, processing, and storing of drugs. As usedherein, the term “drug” is synonymous with “pharmaceutical”. In certainembodiments, the program can be modified to conform to the programminglanguage and operating system requirements of an individual system. In afurther embodiment, the program is used to validate hardware use in drugmanufacture. In another embodiment, the program is used to validatesoftware used in drug manufacture. In another embodiment, the program isused to monitor quality assurance protocols put in place by the qualitycontrol unit.

The invention further provides methods for validating drug manufactureusing the application software. In one embodiment, the method comprisesinstallation during the concept phase of manufacturing. In anotherembodiment, the method comprises installation at which time themanufacture process is on-line. In another embodiment, the methodcomprises installation during the course of quality assurance. Inanother embodiment, the method comprises monitoring the validation andquality assurance based on a routine maintenance schedule.

The invention further comprises a system which integrates applicationsoftware and methods disclosed herein to provide a comprehensivevalidation and quality assurance protocol that is used by a plurality ofend users whereby the data compiled from the system is analyzed and usedto determine is quality assurance protocols and validation protocols arebeing achieved.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Schematic of analysis method.

FIG. 2. Flowchart of Standard Hazard Analysis and Mitigation.

FIG. 3. Schematic of failure analysis method.

DETAILED DESCRIPTION OF THE INVENTION

Outline of Sections

I.) Definitions

II.) Software Program

III.) Analysis

IV.) KITS/Articles of Manufacture

I.) Definitions:

Unless otherwise defined, all terms of art, notations and otherscientific terms or terminology used herein are intended to have themeanings commonly understood by those of skill in the art to which thisinvention pertains unless the context clearly indicates otherwise. Insome cases, terms with commonly understood meanings are defined hereinfor clarity and/or for ready reference, and the inclusion of suchdefinitions herein should not necessarily be construed to represent asubstantial difference over what is generally understood in the art.Many of the techniques and procedures described or referenced herein arewell understood and commonly employed using conventional methodology bythose skilled in the art, such as, for example, the widely utilizedcurrent Good Manufacturing Practice guidelines.

As used herein the terms “drug” and “pharmaceutical” include veterinarydrugs and human drugs, including human biological drug products.

“abstraction” means the separation of the logical properties of data orfunction from its implementation in a computer program.

“access time” means the time interval between the instant at which acall for data is initiated and the instant at which the delivery of thedata is completed.

“accuracy study processor” means a software tool used to performcalculations or determine accuracy of computer manipulated programvariables.

“adaptive maintenance” means software maintenance performed to make acomputer program usable in a changed environment.

“address” means a number, character, or group of characters whichidentifies a given device or a storage location which may contain apiece of data or a program step.

“algorithm” means any sequence of operations for performing a specifictask.

“algorithm analysis” means a software verification and validation (“V &V”) task to ensure that the algorithms selected are correct,appropriate, and stable, and meet all accuracy, timing, and sizingrequirements.

“alphanumeric” means pertaining to a character set that containsletters, digits, and usually other characters such as punctuation marks,etc.

“analog” means pertaining to data [signals] in the form of continuouslyvariable [wave form] physical quantities; e.g., pressure, resistance,rotation, temperature, voltage.

“analog device” means a device that operates with variables representedby continuously measured quantities such as pressures, resistances,rotations, temperatures, and voltages.

“analog-to-digital converter” means input related devices whichtranslate an input device's [sensor] analog signals to the correspondingdigital signals needed by the computer.

“analysis” means a course of reasoning showing that a certain result isa consequence of assumed premises.

“application software” means software designed to fill specific needs ofa user.

“bar code” means a code representing characters by sets of parallel barsof varying thickness and separation that are read optically bytransverse scanning.

“BASIC” means an acronym for Beginners All-purpose Symbolic InstructionCode, a high-level programming language intended to facilitate learningto program in an interactive environment.

“basic input/output system” means firmware that activates peripheraldevices in a PC. Includes routines for the keyboard, screen, disk,parallel port and serial port, and for internal services such as timeand date. It accepts requests from the device drivers in the operatingsystem as well from application programs. It also contains autostartfunctions that test the system on startup and prepare the computer foroperation. It loads the operating system and passes control to it.

“batch processing” means execution of programs serially with nointeractive processing.

“benchmark” means a standard against which measurements or comparisonscan be made.

“bias” means a measure of how closely the mean value in a series ofreplicate measurements approaches the true value.

“block” means a string of records, words, or characters that fortechnical or logical purposes are treated as a unity.

“block check” means the part of the error control procedure that is usedfor determining that a block of data is structured according to givenrules.

“block diagram” means a diagram of a system, instrument or computer, inwhich the principal parts are represented by suitably annotatedgeometrical figures to show both the basic functions of the parts andthe functional relationships between them.

“blueprint” means an detailed plan or outline.

“boot” means to initialize a computer system by clearing memory andreloading the operating system. A distinction can be made between a warmboot and a cold boot. A cold boot means starting the system from apowered-down state. A warm boot means restarting the computer while itis powered-up. Important differences between the two procedures are; 1)a power-up self-test, in which various portions of the hardware [such asmemory] are tested for proper operation, is performed during a cold bootwhile a warm boot does not normally perform such self-tests, and 2) awarm boot does not clear all memory.

“bootstrap” means a short computer program that is permanently residentor easily loaded into a computer and whose execution brings a largerprogram, such an operating system or its loader, into memory.

“boundary value” means a data value that corresponds to a minimum ormaximum input, internal, or output value specified for a system orcomponent.

“boundary value analysis” means a selection technique in which test dataare chosen to lie along “boundaries” of the input domain [or outputrange] classes, data structures, procedure parameters, etc.

“branch analysis” means a test case identification technique whichproduces enough test cases such that each decision has a true and afalse outcome at least once.

“calibration” means ensuring continuous adequate performance of sensing,measurement, and actuating equipment with regard to specified accuracyand precision requirements.

“certification” means technical evaluation, made as part of and insupport of the accreditation process, that establishes the extent towhich a particular computer system or network design and implementationmeet a pre-specified set of requirements.

“change control” means the processes, authorities for, and procedures tobe used for all changes that are made to the computerized system and/orthe system's data. Change control is a vital subset of the QualityAssurance [QA] program within an establishment and should be clearlydescribed in the establishment's SOPs.

“check summation” means a technique for error detection to ensure thatdata or program files have been accurately copied or transferred.

“compiler” means computer program that translates programs expressed ina high-level language into their machine language equivalents.

“computer system audit” means an examination of the procedures used in acomputer system to evaluate their effectiveness and correctness and torecommend improvements.

“computer system security” means the protection of computer hardware andsoftware from accidental or malicious access, use, modification,destruction, or disclosure.

“concept phase” means the initial phase of a software developmentproject, in which user needs are described and evaluated throughdocumentation.

“configurable, off-the-shelf software” means application software,sometimes general purpose, written for a variety of industries or usersin a manner that permits users to modify the program to meet theirindividual needs.

“control flow analysis” means a software V & V task to ensure that theproposed control flow is free of problems, such as design or codeelements that are unreachable or incorrect.

“controller” means hardware that controls peripheral devices such as adisk or display screen. It performs the physical data transfers betweenmain memory and the peripheral device.

“conversational” means pertaining to a interactive system or mode ofoperation in which the interaction between the user and the systemresembles a human dialog.

“coroutine” means a routine that begins execution at the point at whichoperation was last suspended, and that is not required to return controlto the program or subprogram that called it.

“corrective maintenance” means maintenance performed to correct faultsin hardware or software.

“critical control point” means a function or an area in a manufacturingprocess or procedure, the failure of which, or loss of control over, mayhave an adverse affect on the quality of the finished product and mayresult in an unacceptable health risk.

“data analysis” means evaluation of the description and intended use ofeach data item in the software design to ensure the structure andintended use will not result in a hazard. Data structures are assessedfor data dependencies that circumvent isolation, partitioning, dataaliasing, and fault containment issues affecting safety, and the controlor mitigation of hazards.

“data integrity” means the degree to which a collection of data iscomplete, consistent, and accurate.

“data validation” means a process used to determine if data areinaccurate, incomplete, or unreasonable. The process may include formatchecks, completeness checks, check key tests, reasonableness checks andlimit checks.

“design level” means the design decomposition of the software item;e.g., system, subsystem, program or module.

“design phase” means the period of time in the software life cycleduring which the designs for architecture, software components,interfaces, and data are created, documented, and verified to satisfyrequirements.

“diagnostic” means pertaining to the detection and isolation of faultsor failures.

“different software system analysis” means Analysis of the allocation ofsoftware requirements to separate computer systems to reduce integrationand interface errors related to safety. Performed when more than onesoftware system is being integrated.

“dynamic analysis” means analysis that is performed by executing theprogram code.

“encapsulation” means a software development technique that consists ofisolating a system function or a set of data and the operations on thosedata within a module and providing precise specifications for themodule.

“end user” means a person, device, program, or computer system that usesan information system for the purpose of data processing in informationexchange.

“error detection” means techniques used to identify errors in datatransfers.

“error guessing” means the selection criterion is to pick values thatseem likely to cause errors.

“error seeding” means the process of intentionally adding known faultsto those already in a computer program for the purpose of monitoring therate of detection and removal, and estimating the number of faultsremaining in the program.

“failure analysis” means determining the exact nature and location of aprogram error in order to fix the error, to identify and fix othersimilar errors, and to initiate corrective action to prevent futureoccurrences of this type of error.

“Failure Modes and Effects Analysis” means a method of reliabilityanalysis intended to identify failures, at the basic component level,which have significant consequences affecting the system performance inthe application considered.

“FORTRAN” means an acronym for FORmula TRANslator, the first widely usedhigh-level programming language. Intended primarily for use in solvingtechnical problems in mathematics, engineering, and science.

“life cycle methodology” means the use of any one of several structuredmethods to plan, design, implement, test and operate a system from itsconception to the termination of its use.

“logic analysis” means evaluates the safety-critical equations,algorithms, and control logic of the software design.

“low-level language” means the advantage of assembly language is that itprovides bit-level control of the processor allowing tuning of theprogram for optimal speed and performance. For time critical operations,assembly language may be necessary in order to generate code whichexecutes fast enough for the required operations.

“maintenance” means activities such as adjusting, cleaning, modifying,overhauling equipment to assure performance in accordance withrequirements.

“modulate” means varying the characteristics of a wave in accordancewith another wave or signal, usually to make user equipment signalscompatible with communication facilities.

“Pascal” means a high-level programming language designed to encouragestructured programming practices.

“path analysis” means analysis of a computer program to identify allpossible paths through the program, to detect incomplete paths, or todiscover portions of the program that are not on any path.

“quality assurance” means the planned systematic activities necessary toensure that a component, module, or system conforms to establishedtechnical requirements.

“quality control” means the operational techniques and procedures usedto achieve quality requirements.

“software engineering” means the application of a systematic,disciplined, quantifiable approach to the development, operation, andmaintenance of software.

“software engineering environment” means the hardware, software, andfirmware used to perform a software engineering effort.

“software hazard analysis” means the identification of safety-criticalsoftware, the classification and estimation of potential hazards, andidentification of program path analysis to identify hazardouscombinations of internal and environmental program conditions.

“software reliability” means the probability that software will notcause the failure of a system for a specified time under specifiedconditions.

“software review” means an evaluation of software elements to ascertaindiscrepancies from planned results and to recommend improvement.

“software safety change analysis” means analysis of the safety-criticaldesign elements affected directly or indirectly by the change to showthe change does not create a new hazard, does not impact on a previouslyresolved hazard, does not make a currently existing hazard more severe,and does not adversely affect any safety-critical software designelement.

“software safety code analysis” means verification that thesafety-critical portions of the design are correctly implemented in thecode.

“software safety design analysis” means verification that thesafety-critical portion of the software design correctly implements thesafety-critical requirements and introduces no new hazards.

“software safety requirements analysis” means analysis evaluatingsoftware and interface requirements to identify errors and deficienciesthat could contribute to a hazard.

“software safety test analysis” means analysis demonstrating that safetyrequirements have been correctly implemented and that the softwarefunctions safely within its specified environment.

“system administrator” means the person that is charged with the overalladministration, and operation of a computer system. The SystemAdministrator is normally an employee or a member of the establishment

“system analysis” means a systematic investigation of a real or plannedsystem to determine the functions of the system and how they relate toeach other and to any other system.

“system design” means a process of defining the hardware and softwarearchitecture, components, modules, interfaces, and data for a system tosatisfy specified requirements.

“top-down design” means pertaining to design methodology that startswith the highest level of abstraction and proceeds through progressivelylower levels.

“traceability analysis” means the tracing of Software RequirementsSpecifications requirements to system requirements in conceptdocumentation.

“validation” means establishing documented evidence which provides ahigh degree of assurance that a specific process will consistentlyproduce a product meeting its predetermined specifications and qualityattributes.

“validation, process” means establishing documented evidence whichprovides a high degree of assurance that a specific process willconsistently produce a product meeting its predetermined specificationsand quality characteristics.

“validation, prospective” means validation conducted prior to thedistribution of either a new product, or product made under a revisedmanufacturing process, where the revisions may affect the product'scharacteristics.

“validation protocol” means a written plan stating how validation willbe conducted, including test parameters, product characteristics,production equipment, and decision points on what constitutes acceptabletest results.

“validation, retrospective” means validation of a process for a productalready in distribution based upon accumulated production, testing andcontrol data. Retrospective validation can also be useful to augmentinitial premarket prospective validation for new products or changedprocesses. Test data is useful only if the methods and results areadequately specific. Whenever test data are used to demonstrateconformance to specifications, it is important that the test methodologybe qualified to assure that the test results are objective and accurate.

“validation, software” means. determination of the correctness of thefinal program or software produced from a development project withrespect to the user needs and requirements. Validation is usuallyaccomplished by verifying each stage of the software development lifecycle.

“structured query language” means a language used to interrogate andprocess data in a relational database. Originally developed for IBMmainframes, there have been many implementations created for mini andmicro computer database applications. SQL commands can be used tointeractively work with a data base or can be embedded with aprogramming language to interface with a database.

“Batch” means a specific quantity of a drug or other material that isintended to have uniform character and quality, within specified limits,and is produced according to a single manufacturing order during thesame cycle of manufacture.

“Component” means any ingredient intended for use in the manufacture ofa drug product, including those that may not appear in such drugproduct.

“Drug product” means a finished dosage form, for example, tablet,capsule, solution, etc., that contains an active drug ingredientgenerally, but not necessarily, in association with inactiveingredients. The term also includes a finished dosage form that does notcontain an active ingredient but is intended to be used as a placebo.

“Active ingredient” means any component that is intended to furnishpharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease, or to affect thestructure or any function of the body of man or other animals. The termincludes those components that may undergo chemical change in themanufacture of the drug product and be present in the drug product in amodified form intended to furnish the specified activity or effect.

“Inactive ingredient” means any component other than an activeingredient.

“In-process material” means any material fabricated, compounded,blended, or derived by chemical reaction that is produced for, and usedin, the preparation of the drug product.

“Lot number, control number, or batch number” means any distinctivecombination of letters, numbers, or symbols, or any combination thereof,from which the complete history of the manufacture, processing, packing,holding, and distribution of a batch or lot of drug product or othermaterial can be determined.

“Quality control unit” means any person or organizational elementdesignated by the firm to be responsible for the duties relating toquality control.

“Acceptance criteria” means the product specifications andacceptance/rejection criteria, such as acceptable quality level andunacceptable quality level, with an associated sampling plan, that arenecessary for making a decision to accept or reject a lot or batch.

II.) Software Program (Computer Product)

The invention provides for a software program that is programmed in ahigh-level or low-level programming language, preferably a relationallanguage such as structured query language which allows the program tointerface with an already existing program or a database. Preferably,however, the program will be initiated in parallel with themanufacturing process or quality assurance (“QA”) protocol. This willallow the ability to monitor the manufacturing and QA process from itsinception. However, in some instances the program can be bootstrappedinto an already existing program that will allow monitoring from thetime of execution (i.e. bootstrapped to configurable off-the-shelfsoftware).

It will be readily apparent to one of skill in the art that thepreferred embodiment will be a software program that can be easilymodified to conform to numerous software-engineering environments. Oneof ordinary skill in the art will understand and will be enabled toutilize the advantages of the invention by designing the system withtop-down design. The level of abstraction necessary to achieve thedesired result will be a direct function of the level of complexity ofthe process that is being monitored. For example, the critical controlpoint for monitoring an active ingredient versus an inactive ingredientmay not be equivalent. Similarly, the critical control point formonitoring an in-process material may vary from component to componentand often from batch to batch.

One of ordinary skill will appreciate that to maximize results theability to amend the algorithm needed to conform to the validation andQA standards set forth by the quality control unit on each step duringmanufacture will be preferred. This differential approach to programmingwill provide the greatest level of data analysis leading to the higheststandard of data integrity.

The preferred embodiments may be implemented as a method, system, orprogram using standard software programming and/or engineeringtechniques to produce software, firmware, hardware, or any combinationthereof. The term “computer product” as used herein is intended toencompass one or more computer programs and data files accessible fromone or more computer-readable devices, firmware, programmable logic,memory devices (e.g. EEPROM's, ROM's, PROM's, RAM's, SRAM's, etc.)hardware, electronic devices, a readable storage diskette, CD-ROM, afile server providing access to programs via a network transmissionline, wireless transmission media, signals propagating through space,radio waves, infrared signals, etc. Those of skill in the art willrecognize that many modifications may be made without departing from thescope of the present invention.

III.) Analysis

The invention provides for a method of analyzing data that is compiledas a result of the manufacturing of pharmaceuticals. Further theinvention provides for the analysis of data that is compiled as a resultof a QA program used to monitor the manufacture of drugs in order tomaintain the highest level of data integrity. In one embodiment, theparameters of the data will be defined by the quality control unit.Generally, the quality control unit will provide endpoints that need tobe achieved to conform to cGMP regulations or in some instances aninternal endpoint that is more restrictive to the minimum levels thatneed to be achieved.

In a preferred embodiment, the invention provides for data analysisusing boundary value analysis. The boundary value will be set forth bythe quality control unit. Using the boundary values set forth for aparticular phase of manufacture the algorithm is defined. Once thealgorithm is defined, an algorithm analysis (i.e. logic analysis) takesplace. One of skill in the art will appreciate that a wide variety oftools are used to confirm algorithm analysis such as an accuracy studyprocessor.

One of ordinary skill will appreciate that different types of data willrequire different types of analysis. In a further embodiment, theprogram provides a method of analyzing block data via a block check. Ifthe block check renders an affirmative analysis, the benchmark has beenmet and the analysis continues to the next component. If the block checkrenders a negative the data is flagged via standard recognition filesknown in the art and a hazard analysis and hazard mitigation occurs.

In a further embodiment, the invention provides for data analysis usingbranch analysis. The test cases will be set forth by the quality controlunit.

In a further embodiment, the invention provides for data analysis usingcontrol flow analysis. The control flow analysis will calibrate thedesign level set forth by the quality control unit which is generated inthe design phase.

In a further embodiment, the invention provides for data analysis usingfailure analysis. The failure analysis is initiated using the failurebenchmark set forth by the quality control unit and then using standardtechniques to come to error detection. The preferred technique will betop-down. For example, error guessing based on quality control groupparameters which are confirmed by error seeding.

In a further embodiment, the invention provides for data analysis usingpath analysis. The path analysis will be initiated after the designphase and will be used to confirm the design level. On of ordinary skillin the art will appreciate that the path analysis will be a dynamicanalysis depending on the complexity of the program modification. Forexample, the path analysis on the output of an end product will beinherently more complex that the path analysis for the validation of anin-process material. However, one of ordinary skill will understand thatthe analysis is the same, but the parameters set forth by the qualitycontrol unit will differ.

The invention provides for a top-down design to software analysis. Thispreferred embodiment is advantageous because the parameters of analysiswill be fixed for any given process and will be set forth by the qualitycontrol unit. Thus, performing software safety code analysis thensoftware safety design analysis, then software safety requirementsanalysis, and then software safety test analysis will be preferred.

The aforementioned analysis methods are used for several non-limitingembodiments, including but not limited to, validating QA software,validating pharmaceutical manufacturing, and validating process designswherein the integration of the system design will allow for moreefficient determination of acceptance criteria in a batch, in-processmaterial, batch number, control number, and lot number and allow forincreased access time thus achieving a more efficient cost-savingmanufacturing process.

IV.) Kits/Articles of Manufacture

For use in basic input/output systems, hardware calibrations, softwarecalibrations, computer systems audits, computer system securitycertification, data validation, different software system analysis,quality control, and the manufacturing of drug products describedherein, kits are within the scope of the invention. Such kits cancomprise a carrier, package, or container that is compartmentalized toreceive one or more containers such as boxes, shrink wrap, and the like,each of the container(s) comprising one of the separate elements to beused in the method, along with a program or insert comprisinginstructions for use, such as a use described herein.

The kit of the invention will typically comprise the container describedabove and one or more other containers associated therewith thatcomprise materials desirable from a commercial and user standpoint,programs listing contents and/or instructions for use, and packageinserts with instructions for use.

A program can be present on or with the container. Directions and orother information can also be included on an insert(s) or program(s)which is included with or on the kit. The program can be on orassociated with the container.

The terms “kit” and “article of manufacture” can be used as synonyms.

The article of manufacture typically comprises at least one containerand at least one program. The containers can be formed from a variety ofmaterials such as glass, metal or plastic.

EXAMPLES

Various aspects of the invention are further described and illustratedby way of the several examples that follow, none of which is intended tolimit the scope of the invention.

Example 1 Implementation in Clinical Manufacturing Process

In one embodiment, the invention comprises the validation and qualitycontrol of drug products manufactured during the clinical phase ofdevelopment. Generally, A phase I human clinical trial is initiated toassess the safety of doses of a drug product candidate in connectionwith the treatment of a disease. In the study, the safety of singledoses when utilized as therapy is assessed. The trial design includesdelivery of single doses of a drug product candidate escalating fromapproximately about 25 mg/m ² to about 275 mg/m ² over the course of thetreatment in accordance with a pre-defined schedule (i.e. parametersdefined by quality control unit).

Patients are closely followed for one-week following each administrationof the drug product candidate. In particular, patients are assessed forsafety concerns (i.e. toxicity, fever, shaking, chills, the developmentof an immunogenic response to the material.) Standard tests andfollow-up are utilized to monitor each of these safety concerns.Patients are also assessed for clinical outcome and particularlytreatment of the disease being evaluated.

The drug product candidate is demonstrated to be safe and efficacious,Phase II trials confirm the efficacy and refine optimum dosing.

The drug product candidate is safe in connection with theabove-discussed trial, a Phase II human clinical trial confirms theefficacy and optimum dosing for monotherapy. Such trial is accomplished,and entails the same safety and outcome analyses, to the above-describedtrial with the exception being that patients do not receive other formsof treatment concurrently with the receipt of doses of the drug productcandidate.

Once again, as the therapy discussed above is safe within the safetycriteria discussed above, a Phase III human clinical trial is initiated.

As previously set forth, the acceptance criteria of all components usedin the drug product manufacture for the purposes of the clinical trialare determined by the quality control unit. The analysis of the softwareand hardware occurs using any of the methods disclosed herein. (See forexample FIG. 1 and FIG. 3). The program monitors and processes the dataand stores the data using standard methods. The data is provided to anend user or a plurality of end users for assessing the quality of thebatch. Furthermore, the data is stored for comparative analysis toprevious batches to provide a risk-based assessment in case of failure.Using the historical analysis will provide a more streamlinedmanufacturing approach and will provide cost-saving over time. Inaddition, the invention comprises monitoring the data from initialprocess, monitoring the data at the end process, and monitoring the datafrom a routine maintenance schedule to ensure the system maintain dataintegrity and validation standard predetermined by the quality controlunit.

Example 2 Implementation in Post-Clinical Commercial ManufacturingProcess

Provided the drug product candidate has been awarded regulatory approvaland is manufactured for commercial use. The invention comprises a methodfor monitoring the acceptance criteria of all components used in thedrug product manufacture. The analysis of the software and hardwareoccurs using any of the methods disclosed herein. (See for example FIG.1 and FIG. 3). The program monitors and processes the data and storesthe data using methods known in the art. The data is provided to an enduser or a plurality of end users for assessing the quality of the batch.Furthermore, the data is stored for comparative analysis to previousbatches to provide a risk-based assessment in case of failure. Using thehistorical analysis will provide a more streamlined manufacturingapproach and will provide cost-saving over time. In addition, theinvention comprises monitoring the data from initial process, monitoringthe data at the end process, and monitoring the data from a routinemaintenance schedule to ensure the system maintain data integrity andvalidation standard predetermined by the quality control unit.

Example 3 Integration of Program into Manufacturing Hardware System

The invention comprises the integration of the computer product into amanufacturing hardware system. In this context, the term “hardware”means any physical device used in the pharmaceutical manufacturingprocess including, but not limited to, blenders, bio-reactors, cappingmachines, chromatography/separation systems, chilled water/circulating,glycol, coldrooms, clean steam, clean-in-place (CIP), compressed air,D.I./R.O. watersystems, dry heat sterilizers/ovens, fermentationequipment/bio reactors, freezers, filling equipment,filtration/purification, HVAC: environmental controls,incubators/environmentally controlled chambers, labelers,lyophilizers/freeze, dryers, mixing tanks, modular cleanrooms,neutralization systems, plant steam and condensate, processtanks/pressure, vessels, refrigerators, separation/purificationequipment, specialty gas, systems, steam generators/pure steam systems,steam sterilizers, stopper washers, solvent recovery systems, towerwater systems, waste inactivation systems/“kill” systems, vialinspection systems, vial washers, water for injection (WFI) systems,pure water systems, washers (glass, tank, carboys, etc.).

It will be understood by one of skill in the art that the computerproduct integrates the hardware via generally understood devices in theart (i.e. attached to the analog device via an analog to digitalconverter).

The computer product is integrated into the manufacturing system on adevice by device basis. As previously set forth, the acceptance criteriaof all devices used in the drug product manufacture for the purposes ofthe manufacturing process are determined by the quality control unit.The analysis of the software and hardware occurs using any of themethods disclosed herein. (See for example FIG. 1 and FIG. 3). Theprogram monitors and processes the data and stores the data usingstandard methods. The data is provided to an end user or a plurality ofend users for assessing the quality of data generated by the device.Furthermore, the data is stored for comparative analysis to previousbatches to provide a risk-based assessment in case of failure. Using thehistorical analysis will provide a more streamlined manufacturingapproach and will provide cost-saving over time. In addition, theinvention comprises monitoring the data from initial process, monitoringthe data at the end process, and monitoring the data from a routinemaintenance schedule to ensure the system maintain data integrity andvalidation standard predetermined by the quality control unit.

Example 4 Integration of Program into Manufacturing Software System

The invention comprises the integration of the computer product into amanufacturing software system. In this context, the term “software”means any device used in the pharmaceutical manufacturing processincluding, but not limited to user-independent audit trails,time-stamped audit trails, data security, confidentiality systems,limited authorized system access, electronic signatures, bar codes,dedicated systems, add-on systems, control files, Internet, LAN's, etc.

The computer product is integrated into the manufacturing system on adevice-by-device basis. As previously set forth, the acceptance criteriaof all devices used in the drug product manufacture for the purposes ofthe manufacturing process are determined by the quality control unit.The analysis of the software and hardware occurs using any of themethods disclosed herein. (See for example FIG. 1 and FIG. 3). Theprogram monitors and processes the data and stores the data usingstandard methods. The data is provided to an end user or a plurality ofend users for assessing the quality of data generated by the device.Furthermore, the data is stored for comparative analysis to previousbatches to provide a risk-based assessment in case of failure. Using thehistorical analysis will provide a more streamlined manufacturingapproach and will provide cost-saving over time. In addition, theinvention comprises monitoring the data from initial process, monitoringthe data at the end process, and monitoring the data from a routinemaintenance schedule to ensure the system maintain data integrity andvalidation standard predetermined by the quality control unit.

Example 5 Integration of Program into Quality Assurance System

The invention comprises the integration of the computer product into aquality assurance system. In this context, the term “quality assurance”means the planned systematic activities necessary to ensure that acomponent, module, or system conforms to established technicalrequirements. A quality assurance system will compliment either of thesystems set for in the examples entitled “Integration of program intomanufacturing hardware system” or “Integration of program intomanufacturing software system” to ensure data integrity and reliabilityfrom the data that is generated set forth in either of the examplesentitled “Implementation in Clinical Manufacturing Process”or“Implementation in Post-Clinical Commercial Manufacturing Process”.

The computer product is integrated into the manufacturing system on adevice-by-device basis. As previously set forth, the acceptance criteriaof all devices used in the drug product manufacture for the purposes ofthe manufacturing process are determined by the quality control unit.The analysis of the software and hardware occurs using any of themethods disclosed herein. (See for example FIG. 1 and FIG. 3). Theprogram monitors and processes the data and stores the data usingstandard methods. The data is provided to an end user or a plurality ofend users for assessing the quality of data generated by the device.Furthermore, the data is stored for comparative analysis to previousbatches to provide a risk-based assessment in case of failure. Using thehistorical analysis will provide a more streamlined manufacturingapproach and will provide cost-saving over time. In addition, theinvention comprises monitoring the data from initial process, monitoringthe data at the end process, and monitoring the data from a routinemaintenance schedule to ensure the system maintain data integrity andvalidation standard predetermined by the quality control unit.

Example 6 Integration of Program and Methods into a ComprehensiveCost-Saving System

The invention comprises a program and method integrated into acomprehensive cost-saving pharmaceutical manufacturing system. A user,preferably a system administrator, logs onto the system via secure means(i.e. password or other security measures known in the art) and inputsthe boundary values for a particular component of the drug manufacturingprocess. The input is at the initial stage, the end product state, orany predetermined interval in between that has been established forroutine maintenance by the quality control unit. The data is generatedusing any one of the various analysis methods described herein (aspreviously stated the type of analysis used is functional to the deviceor protocol being monitored or evaluated). Subsequent to the dataanalysis, any modifications or corrective action to the manufacturingprocess is implemented. The data is then stored by standard methodsknown in the art. Scheduled analysis of the stored data is maintained toprovide a preventative maintenance of the manufacturing process. Overtime, costs are reduced due to the tracking of data and analysis oftroubled areas and frequency of hazards that occur on any given devicein the manufacturing process. The system is implemented on every devicewhich plays a role in drug manufacturing. The data compiled from everydevice is analyzed using the methods described herein.

The present invention is not to be limited in scope by the embodimentsdisclosed herein, which are intended as single illustrations ofindividual aspects of the invention, and any that are functionallyequivalent are within the scope of the invention. Various modificationsto the models and methods of the invention, in addition to thosedescribed herein, will become apparent to those skilled in the art fromthe foregoing description and teachings, and are similarly intended tofall within the scope of the invention. Such modifications or otherembodiments can be practiced without departing from the true scope andspirit of the invention.

1) A method of integrating a computer product with a pharmaceuticalmanufacturing system said method comprising, a) contacting the computerproduct to a software device used in pharmaceutical manufacture; b)monitoring the data generated by the software device used inpharmaceutical manufacture; c) maintaining the data over time to providea historical record; d) analyzing the historical record to provide arisk-based assessment in case of failure; e) taking corrective action toobviate the failure. 2) The method of claim 1, wherein the softwaredevice is selected from the group consisting of audit trails, datasecurity, limited authorized access, electronic signatures, bar codes,web-based systems, LAN's, and wireless systems. 3) The method of claim1, whereby the integration occurs at initial process. 4) The method ofclaim 1, whereby the integration occurs at end process. 5) The method ofclaim 1, wherein the monitoring is part of routine maintenance. 6) Themethod of claim 1, wherein the data is generated by an analysis selectedfrom the group consisting of boundary value analysis, branch analysis,control flow analysis, failure analysis, and path analysis. 7) Asoftware program which performs the method of claim
 1. 8) A kitcomprising the software program of claim 7.